The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the “cholinergic anti-inflammatory pathway”. Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

Indiana University-Purdue University Indianapolis (IUPUI) / This thesis describes a novel method to reversibly and safely block nerve conduction using a low frequency alternating current (LFAC) waveform at 1 Hz applied through a bipolar extrafascicular electrode. This work follows up on observations made on excised mammalian peripheral nerves and earthworm nerve cords. An in-situ electrophysiology setup was used to assess the LFAC waveform on propagating action potentials (APs) within the cervical vagus nerve in anaesthetized Sprague-Dawley rats (n = 12). Two sets of bipolar cuff or hook electrodes were applied unilaterally to the cervical vagus nerve, which was crushed rostral to the electrodes to exclude reflex effects on the animal. Pulse stimulation was applied to the rostral electrode, while the LFAC conditioning waveform was applied to the caudal electrode. The efferent volley, if unblocked, elicits acute bradycardia and hypotension. The degree of block of the vagal stimulation induced bradycardia was used as a biomarker. Block was assessed by the ability to reduce the bradycardic drive by monitoring the heart rate (HR) and blood pressure (BP) during LFAC alone, LFAC with vagal stimulation, and vagal stimulation alone. LFAC applied via a hook electrode (n = 7) achieved 86.6 +/- 11% block at current levels 95 +/- 38 uAp (current to peak). When applied via a cuff electrode (n = 5) 85.3 +/- 4.60% block was achieved using current levels of 110+/-65 uAp. Furthermore, LFAC was explored on larger vagal afferent fibers in larger human sized nerve bundles projecting to effects mediated by a reflex. The effectiveness of LFAC was assessed in an in-situ electrophysiological setup on the left cervical vagus in anaesthetized domestic swine (n = 5). Two bipolar cuff electrodes were applied unilaterally to the cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar extrafascicular cuff electrode was placed most rostral on the nerve for recording of propagating APs induced by electrical stimulation and blocked via the LFAC waveform. Standard pulse stimulation was applied to the left cervical vagus to induce the Hering-Breuer reflex. If unblocked, the activation of the Hering-Breuer reflex would cause breathing to slow down and potentially cease. Block was quantified by the ability to reduce the effect of the Hering-Breuer reflex by monitoring the breathing rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. LFAC achieved 87.2 +/- 8.8% (n = 5) block at current levels of 0.8 +/- 0.3 mAp. Compound nerve action potentials (CNAP) were monitored directly. They show changes in nerve activity during LFAC, which manifests itself as the slowing and amplitude reduction of components of the CNAPs. Since the waveform is balanced, all forward reactions are reversed, leading to a blocking method that is similar in nature to DC block without the potential issues of toxic byproduct production. These results suggest that LFAC can achieve a high degree of nerve block in both small and large nerve bundles, resulting in the change in behavior of a biomarker, in-vivo in the mammalian nervous system at low amplitudes of electrical stimulation that are within the water window of the electrode.

No description available.

Context: Knee pain is a common symptom in knee pathology and is associated with alterations in quadriceps activation and movement patterns. Reducing pain through intervention may help reestablish neuromuscular function. The independent effects of knee pain are difficult to examine and unclear. Objective: To investigate the effects of transcutaneous electrical nerve stimulation (TENS) on quadriceps activation and vertical ground reaction force (VGRF) during walking. Design: Crossover. Setting: Laboratory. Subjects: 15 in the TENS group (10M and 5F, 23.5 ± 2.8 yrs, 70.5 ± 12.5 kg, 178.1 ± 7.4 cm), and 15 in the sham group (10M and 5F, 22.5 ± 2.0 yrs, 72.1 ± 13.7 kg, 177.5 ± 9.3 cm). Interventions: Subjects underwent three experimental conditions (pain, sham, and control). Measurements were recorded across four time points (preinfusion, infusion, treatment, and posttreatment). Hypertonic or isotonic saline, respectively, was infused into the infrapatellar fat pad for 48 minutes (total 7.7 mL). The TENS group received a 20-minute treatment. A sham treatment was administered to the sham group. Main Outcome Measures: Perceived knee pain on a 10-cm visual analog scale, knee extension maximum voluntary isometric contraction (MVIC) normalized to body mass, knee extension central activation ratio (CAR), and VGRF. Results: Knee pain peaked at 4 cm during infusion and remained consistent across time in the sham group (F2,28 = 49.90, P < 0.0001), while knee pain gradually decreased to 1.5 cm following TENS treatment (F2,28 = 23.11, P < 0.0001). A group x condition x time interaction was detected for both the MVIC (F6,168 = 2.92, P < 0.01) and CAR (F6,168 = 3.03, P < 0.008) measurements. Post hoc analysis revealed that the infusion of hypertonic saline reduced knee extension MVIC by 29% in the TENS group, and by 26% in the sham group (P < 0.05). However, while the MVIC remained depressed by 26% following sham treatment, the MVIC was found to improve by 12% following TENS treatment (P < 0.05). Similarly, a 10% decrease in CAR was detected in both sham and TENS groups prior to treatment. This 10% deficit held, with a 9% deficit following sham treatment, while the deficit of CAR was improved by 4% following TENS treatment (P < 0.05). For the TENS group, infusion of hypertonic saline changed VGRF at initial loading, midstance, and push-off phase. VGRF was only different at initial loading and push-off phase following TENS treatment. For the sham group however, sham treatment did not restore VGRF, showing alterations in initial loading, midstance, and push-off phase (α = 0.05). Conclusions: Infusion of hypertonic saline increased perceived knee pain, reduced knee extension MVIC, reduced CAR, and altered VGRF over some of stance phase. TENS lessened the deficits in MVIC, CAR, and VGRF, suggesting decreased muscle inhibition and improved movement function.

The main objective of this project was to develop a method for soft neural probe insertion into a nerve. These soft probes are made of a silicon elastomer that is a few orders of magnitude less stiff than the nerve, which makes the insertion process particularly challenging. To overcome this challenge a tungsten microwire was used as an insertion shuttle to help penetrate the nerve by increasing the overall stiffness of the probe. At a first stage, the insertion process was tested on a nerve phantom (e.g. agarose gel with PDMS membrane) to control the insertion parameters and validate the insertion platform. Once the envisioned insertion method was established, the probe was implanted in a real rodent nerve. / <p>Examensarbetet är utfört vid Institutionen för teknik och naturvetenskap (ITN) vid Tekniska fakulteten, Linköpings universitet</p>

Bakgrund: Muntorrhet är vanligt förekommande i den vuxna befolkningen och epidemiologiska studier visar att dess förekomst ökar med åldern vilket leder till att salivproduktionen minskar, vilket är en följd av systemiska sjukdomar, läkemedel och strålbehandling av huvud- och halscancer. Syftet: Syftet med studien var att beskriva olika åtgärder som finns för att lindra muntorrhet hos vuxna. Metod: Studien har genomförts i form av en litteraturstudie med kvantitativ metod. Vetenskapliga artiklarna söktes efter i tre olika databaser med totalt 21 artiklar som redovisades i en artikelmatris. Artiklarna publicerades mellan 2000–2021 och åldersgräns &gt;18 år. Resultat: Resultatet har visat flera olika metoder och åtgärder för att lindra och motverka muntorrhet hos vuxna individer. Bland de åtgärderna har läkemedel, salivstimulerade tugg- och sugtabletter, munspray/gel samt akupunkur, elektrisk nervstimulering och LLLT använts. Slutsats: Litteraturstudien har redovisat olika metoder som finns för att lindra muntorrhet hos vuxna människor men nya studier behövs för att förstärka resultatet samt komma fram till fler metoder för att lindra muntorrhet. / Abstract: Dry mouth is common in the adult population and epidemiological studies show that its prevalence increases with age leading to a decrease in saliva production, which is a consequence of systemic diseases, drugs and radiotherapy for head- and neck cancer. Aim: The aim of this study is to describe the various measures available to alleviate dry mouth in adults. Method: The study was conducted as a literature review using quantitative methods. The scientific articles were searched in three different databases, a total of 21 articles presented in an article matrix table. The articles were published between 2000-2021 and the age limit was &gt;18 years. Result: The results have shown several different methods and measures to alleviate and counteract dry mouth in adults. Among those measures, medications; pilocarpine and cervemelin, saliva stimulated tablets, mouth spray/gel as well as Acupuncture, TENS and LLLT have been used. Conclusion: The literature review has reported various methods available to alleviate dry mouth in adults, but new studies are needed to strengthen the results and more methods to alleviate dry mouth.

Irreversible electroporation (IRE) is a non-thermal tissue ablation modality in which electrical pulses are used to generate targeted disruption of cellular membranes. Clinically, IRE is administered by inserting one or more needles within or around a region of interest, then applying a series of short, high amplitude pulsed electric fields (PEFs). The treatment effect is dictated by the local field magnitude, which is quite high near the electrodes but dissipates exponentially. When cells are exposed to fields of sufficient strength, nanoscale "pores" form in the membrane, allowing ions and macromolecules to rapidly travel into and out of the cell. If enough pores are generated for a substantial amount of time, cell homeostasis is disrupted beyond recovery and cells eventually die. Due to this unique non-thermal mechanism, IRE generates targeted cell death without injury to extracellular proteins, preserving tissue integrity. Thus, IRE can be used to treat tumors precariously positioned near major vessels, ducts, and nerves. Since its introduction in the late 2000s, IRE has been used successfully to treat thousands of patients with focal, unresectable malignancies of the pancreas, prostate, liver, and kidney. It has also been used to decellularize tissue and is gaining attention as a cardiac ablation technique. Though IRE opened the door to treating previously inoperable tumors, it is not without limitation. One drawback of IRE is that pulse delivery results in intense muscle contractions, which can be painful for patients and causes electrodes to move during treatment. To prevent contractions in the clinic, patients must undergo general anesthesia and temporary pharmacological paralysis. To alleviate these concerns, high-frequency irreversible electroporation (H-FIRE) was introduced. H-FIRE improves upon IRE by substituting the long (~100 µs) monopolar pulses with bursts of short (~1 µs) bipolar pulses. These pulse waveforms substantially reduce the extent of muscle excitation and electrochemical effects. Within a burst, each pulse is separated from its neighboring pulses by a short delay, generally between 1 and 5 µs. Since its introduction, H-FIRE burst waveforms have generally been constructed simply by choosing the duration of constitutive pulses within the burst, with little attention given to this delay. This is quite reasonable, as it has been well documented that pulse duration plays a critical role in determining ablation size. In this dissertation, we explore the role of these latent periods within burst waveforms as well as their interaction with other pulse parameters. Our central hypothesis is that tuning the latent periods will allow for improved ablation size with reduced muscle contractions over traditional waveforms. After gaining a simple understanding of how pulse width and delay interact in vitro, we demonstrate theoretically that careful tuning of the delay within (interphase) and between (interpulse) bipolar pulses in a burst can substantially reduce nerve excitation. We then analyze how pulse duration, polarity, and delays affect the lethality of burst waveforms toward determining the most optimal parameters from a clinical perspective. Knowing that even the most ideal waveform will require slightly increased voltages over what is currently used clinically, we compare the clinical efficacy of two engineered thermal mitigation strategies to determine what probe design modifications will be needed to successfully translate H-FIRE to the clinic while maintaining large, non-thermal ablation volumes. Finally, we translate these findings in two studies. First, we demonstrate that burst waveforms with an improved delay structure allow for enhanced safety and larger ablation volumes in vivo. And finally, we examine the efficacy of H-FIRE in spontaneous canine liver tumors while also comparing the ablative effect of H-FIRE in tumor and non-neoplastic tissue in a veterinary clinical setting. / Doctor of Philosophy / Cancer is soon to become the most common cause of death in the United States. In 2023, approximately 2 million new cases of cancer will be diagnosed, leading to roughly 650 thousand lost lives. Interestingly, about half of newly diagnosed cancers are caught in the early stages before the disease has spread throughout the body. With effective local intervention, these patients could potentially be cured of their malignancy. Surgical removal of the tumor is the gold standard, but it is often not possible due to tumor location, patient comorbidities, or organ health status. In some instances, focal thermal ablation with radiofrequency or microwave energy can be performed when resection is not possible. These treatments entail the delivery of thermal energy through a needle electrode, which causes local tissue damage through coagulation (cooking) of the tissue. However, thermal ablation destroys tissue indiscriminately, meaning that any nearby blood vessels or neural components will also be damaged, which precludes thousands of patients from treatment each year. Irreversible electroporation (IRE) was introduced to overcome these challenges and provide a treatment option for patients diagnosed with otherwise untreatable tumors. IRE uses pulsed electric fields to generate nanoscale pores in cell membranes, which lead to a homeostatic imbalance and cell death. Because IRE is a membrane-based effect, it does not rely on thermal effects to generate cellular injury, which allows it to be administered to tumors that are adjacent to critical tissue structures such as major nerves and vasculature. Though IRE opened the door to treating otherwise inoperable tumors, procedures are technically challenging and require specialized anesthesia protocols. High-frequency irreversible electroporation (H-FIRE) was introduced by our group roughly a decade ago to simplify the procedure through the use of an alternate pulsing strategy. These higher frequency pulses offer several advantages such as limiting muscle contractions and reducing the risk of cardiac interference, both of which were concerns with IRE. However, H-FIRE ablations have been limited in size, and there is limited knowledge regarding the optimal pulsing strategy needed in order to maximize the ratio of therapeutic benefits to undesirable side effects like muscle stimulation and Joule heating. In this dissertation, we sought to understand how different pulse parameters affect these outcomes. Using a combination of computational, benchtop, and in vivo experiments, we comprehensively characterized the behavior of user-tunable pulse parameters and identified optimal methods for constructing H-FIRE protocols. We then translated our findings in a proof-of-principle study to demonstrate the ability of newly introduced waveform designs to increase ablation size with H-FIRE. Overall, this dissertation improves our understanding of how H-FIRE waveform selection affects clinical outcomes, introduces a new strategy for maximizing therapeutic outcomes with minimal side effects, and provides a framework for selecting parameters for specific applications.

<p>Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy that kills 1̃2 of every 10,000 epileptic patients every year. SUDEP has proven difficult to study because it frequently occurs unobserved and cannot be predicted. What limited clinical data exists suggests that SUDEP occurs as a cardiorespiratory collapse immediately following a seizure. In this work, I explore how a group of autonomic reflexes termed collectively as “oxygen‐conserving reflexes (OCRs)” lead to sudden death when activated during seizures. I also demonstrate multiple physiological parallels between the OCR‐mediated deaths that I report and the clinical data on cases of human SUDEP. Additionally, I explore the neural pathway underlying OCRs, identify the carotid body as a potential target for intervention, and demonstrate the efficacy of electroceutical intervention in reducing the mortality risk of OCR activation during seizures. This work seeks to both offer a neural explanation for SUDEP as well as present a promising target and means for potential intervention.</p>

La neurostimulation périphérique (en anglais transcutaneous electrical nerve stimulation ou TENS) est une modalité thérapeutique fréquemment utilisée en réadaptation pour diminuer la douleur. À ce jour, cependant, l’efficacité analgésique du TENS chez les aînés demeure peu documentée. La majorité des études effectuées jusqu’à présent ont été réalisées chez les jeunes adultes ou chez des populations d’âge hétérogènes. La présente étude, un essai croisé randomisé à double insu, avait pour objectif de documenter l’efficacité analgésique du TENS conventionnel et du TENS acupuncture chez les aînés et d’observer si la réponse analgésique de ces deux modalités de TENS entre les aînés et les jeunes adultes est différente. Quinze aînés et quinze jeunes adultes ont participé à l’étude. Les participants étaient évalués à trois occasions distinctes pour recevoir en alternance un TENS conventionnel, un TENS acupuncture et un TENS placebo. Une douleur expérimentale était créée à l’aide d’une thermode de type Peltier, appliquée au niveau de la colonne lombaire pendant deux minutes, période durant laquelle les participants devaient évaluer l’intensité de leur douleur avec une échelle visuelle analogue reliée à un ordinateur (CoVAS). Les mesures de douleur ont été prises avant, pendant et après l’application de chaque type de TENS. Chez les jeunes adultes, lorsque comparée au niveau de douleur initiale, une diminution significative de la douleur a été observée pendant et après l’application du TENS conventionnel et acupuncture. Le TENS conventionnel et acupuncture étaient supérieurs au traitement placebo (toutes les valeurs de p < 0,05). Cependant, chez les aînés, le TENS conventionnel et acupuncture n’ont pas permis de diminuer significativement la douleur. De plus, aucune modalité TENS ne se démarquait du traitement placebo (toutes les valeurs de p > 0,05). Bien que le TENS conventionnel et le TENS acupuncture soient efficaces chez les jeunes adultes, les présents résultats suggèrent que le TENS n’est pas la meilleure option de traitement pour diminuer la douleur chez les aînés, du moins lorsqu’il est utilisé seul (monothérapie). Des études futures, visant à déterminer des façons de bonifier l’effet du TENS chez les aînés, sont nécessaires.

No description available.